Important progress has been made over the past decade or two in identifying molecular adaptations that occur in specific brain regions in response to chronic administration of drugs of abuse. It also has been possible, by use of genetic mutant mice and related approaches, to directly implicate some of these molecular adaptations in specific behavioral features of addiction. There is a relative paucity of information, however, about the changes in synapses and circuits that occur as a consequence of these drug-induced molecular changes. This information is critical for a thorough understanding of the neural mechanisms of addiction. By combining viral-mediated gene transfer and cellular electrophysiological recording techniques, this Project will examine changes in synaptic and membrane properties of VTA (ventral tegmental area) and NAc (nucleus accumbens) neurons elicited by known molecular adaptations in these neurons studied in the other Projects. These adaptations include certain glutamate receptor subunits and transcription factors, which have been shown to have significant effects in the VTA-NAc pathway on the rewarding responses to drugs of abuse. Specifically, one set of experiments will examine the effects of expressing wildtype or mutant forms of the AMPA receptor subunits GluR1 and GluR2 on excitatory synaptic transmission and plasticity in the VTA and NAc. These experiments will enhance our understanding of the molecular mechanisms underlying the changes in neural circuit function that have been observed in these structures following in vivo drug administration. A second set of experiments will examine the effects of expressing the transcription factors deltaFosB or CREB, or dominant negative mutants of these proteins, on the synaptic and excitability properties of NAc medium spiny neurons and of VTA dopamine and GABAergic neurons. In this way, Project 2 fills a critical gap that has existed in our Program Project Grant up to this point: connecting molecular adaptations and complex behavior. Results from the proposed experiments will provide essential information about the cellular and synaptic changes that occur as a consequence of drug-induced changes in gene expression in the VTA and NAc. This knowledge will in turn help us understand, at an increasingly sophisticated level, the neural mechanisms underlying the complex behavioral abnormalities that characterize drug abuse and addiction.